Escitalopram is the S-enantiomer of an antidepressant drug Citalopram of Formula II.

Citalopram is a well known antidepressant drug that has now been in the market for several years and is chemically known as 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.
Citalopram is a selective centrally acting serotonin (5-HT) reuptake inhibitor. Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193.
The antidepressant activity of Citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychophannacol & Biol. Psychiat., 1982, 6, 277-295 and A. Grravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
The process for the preparation of antidepressant Citalopram and its pharmaceutical properties were first disclosed in U.S. Pat. No. 4,136,193. Citalopram was produced from the corresponding 5-bromo derivative by reaction with cuprous cyanide. Further, variants of this method are disclosed in PCT Publications, WO 00/13648 and WO 00/11926 wherein the exchange of 5-halogen or 5-CF3—(CF2)n—SO2—O— with cyano group is achieved with cyanide source such as KCN, NaCN or (R′4N)CN, where R′4 indicates four groups which may be same or different and are selected from hydrogen and straight chain or branched C1-6 alkane, in presence of palladium or nickel catalyst.
The diol, 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile (VI), and its use as an intermediate in the preparation of Citalopram has been disclosed in U.S. Pat. No. 4,650,884. In this reference, 5-cyanophthalide of Formula III is reacted successively with p-fluorophenylmagnesium bromide and 3-(N,N-dimethylamino)propylmagnesium chloride to get the compound of the Formula VI and its further conversion to Citalopram base is achieved by reaction with 70% sulfuric acid.

The S-enantiomer (Escitalopram) of the Formula I and the antidepressant effect of said enantiomer is disclosed in U.S. Pat. No. 4,943,590, wherein use of Escitalopram for the treatment of neurotic disorders has been described. WO 02/087566 describes the use of Escitalopram for treating depressive patients who have failed to respond to conventional SSRIs.
Escitalopram has now been developed as an antidepressant and hence a need for a commercially feasible method to produce Escitalopram has emerged.
Process for the preparation of Escitalopram was first disclosed in U.S. Pat. No. 4,943,590. According to this patent reference, attempts to resolve Citalopram enantiomers to produce Escitalopram were not successful. Therefore, resolution of enantiomers of the diol compound (VI) with optically active selective precipitant, Di-p-toluoyl-D-tartaric acid, has been carried out to obtain (S)-Enantiomer of Diol prior to ring closure in a stereospecific manner to obtain Escitalopram (I) as shown below:

The resolution of enantiomers requires high purity of Diol compound (VI) to selectively precipitate out (S)-Diol hemi Di-p-toluoyl-D-tartaric acid salt having substantially high chiral purity. The Diol compound (VI), obtained as described in U.S. Pat. No. 4,650,884, is not sufficiently pure and extensive purification steps have been described in this reference, which involve repeated charcoal and silica gel treatment of the Diol compound. Further, purification of Diol compound has been carried out by preparing hydrobromide salt and subsequently by crystallization, first from water and thereafter from 2-propanol/ethanol.
The present invention provides a simple and economical process for the purification of Diol compound (VI), which can be used for commercial production of Escitalopram.